KIR3DL3-HHLA2 is a human immunosuppressive pathway and a therapeutic target

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Science Immunology  09 Jul 2021:
Vol. 6, Issue 61, eabf9792
DOI: 10.1126/sciimmunol.abf9792

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KIR3DL3-HHLA2 interactions protect tumors

HHLA2 (a B7 family member) has both immune inhibitory and activating abilities and is expressed in many human cancers. These differing functions rely on the receptor to which it binds, yet many of these receptors are uncharacterized. Here, Wei et al. found that KIR3DL3 bound to HHLA2 and was expressed on effector memory CD8+ T cells and CD56dim NK cells. Interactions of KIR3DL3 with tumoral HHLA2 inhibited the function and killing capacity of both CD8+ T cells and NK cells. KIR3DL3+ immune cells infiltrated various types of HHLA2+ tumors from patients with cancer, and blockade of KIR3DL3 inhibited the growth of tumors in various mouse models. Thus, KIR3DL3-HHLA2 inhibits immune-mediated clearance of tumor cells and presents a possible immunotherapeutic target for cancer.


The B7 family ligand HERV-H LTR–associating protein 2 (HHLA2) is an attractive target for cancer immunotherapy because of its coinhibitory function, overexpression in human cancers, and association with poor prognoses. However, the knowledge of the HHLA2 pathway is incomplete. HHLA2 has an established positive receptor transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) but a poorly characterized negative receptor human killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3). Here, KIR3DL3 and TMIGD2 simultaneously bound to different sites of HHLA2. KIR3DL3 was mainly expressed on CD56dim NK and terminally differentiated effector memory CD8+ T (CD8+ TEMRA) cells. KIR3DL3+ CD8+ TEMRA acquired an NK-like phenotype and function. HHLA2 engagement recruited KIR3DL3 to the immunological synapse and coinhibited CD8+ T and NK cell function and killing, inducing immune-evasive HHLA2+ tumors. KIR3DL3 recruited SHP-1 and SHP-2 to attenuate Vav1, ERK1/2, AKT, and NF-κB signaling. HHLA2+ tumors from human kidney, lung, gallbladder, and stomach were infiltrated by KIR3DL3+ immune cells. KIR3DL3 blockade inhibited tumor growth in multiple humanized mouse models. Thus, our findings elucidated the molecular and cellular basis for the inhibitory function of KIR3DL3, demonstrating that the KIR3DL3-HHLA2 pathway is a potential immunotherapeutic target for cancer.

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